Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation

Interplay between histone acetylation/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro

“…In this study, we show that the mild increase in acetylation induced by NMDA preconditioning is associated with a downstream increase in ERK 1/2 phosphorylation, a crucial prosurvival signaling pathway in models of ischemic tolerance (Shamloo et al, 1999;Choi et al, 2006;Gao et al, 2010;Gerace et al, 2012). Similarly, Sinn and colleagues (Sinn et al, 2007) have reported that increased acetylation by the HDAC inhibitor valproate activates the translation of pERK in a model of intracerebral hemorrhage. On the other hand, the dramatic increase in acetylation evoked by SAHA prevented the development of OGD tolerance in our model and was associated with an increase in the expression of the death promoter stress-activated kinase SAPK/JNK and CA1 pyramidal cell death in hippocampal slices.…”

“…Similarly, the link between NMDA receptor stimulation (Levenson et al, 2004) or PARP-1 activation (Cohen-Armon et al, 2007) and histone acetylation has been demonstrated to require the phosphorylation of ERK. Although in the latter two studies histone acetylation takes place downstream of Erk phosphorylation, it has also been reported that acetylation may precede the activation of pERK (Sinn et al, 2007), as it appears to occur in our experimental model. In conclusion, our results suggest that under conditions of lethal cellular stress, such as those evoked by cerebral ischemia, there is dramatic reduction in histone acetylation that is responsible for neuronal death, whereas, following exposure to a sublethal preconditioning stimulus that leads to the development of ischemic tolerance, mild activation of PARP and histone acetylation (with a possible concomitant reduction in histone deacetylation) cooperate in producing a neuroprotective response.…”

Minocycline but not valproic acid influence the density of NogoA-immunoreactive neurons in the hilus of the dentate gyrus of the rats subjected to intracerebral haematoma

“…Existing data on mouse model of intracerebral haemorrhage (induced by collagenase injections) suggests that the administration of valproic acid inhibits haematoma expansion, perihaematomal cell death, caspase activation and inflammatory cell infiltration which results in behavioural improvement tested 4 weeks later [38]. Similar effects (on infarct volume, inflammation or behavioural outcome) were observed in murine models of ischaemic stroke [21,36] or traumatic brain injury [6].…”

Neuroprotection by Valproic Acid in Mouse Models of Permanent and Transient Focal Cerebral Ischemia

“…In animal models, treatment with VPA decreases brain infarct volume and neurological deficits in a permanent middle cerebral artery occlusion (pMCAO) model [6] and a transient (tMCAO) model in rats [7]. VPA also reduced hemorrhage volume and hemispheric atrophy and promoted functional recovery in rat intracerebral hemorrhage model [8]. These results suggest that VPA could be used as a neuroprotective agent for ischemic stroke.…”